Is PLEC p.Ser386Arg (c.1158C>G) pathogenic?

PLEC p.Ser386Arg (c.1158C>G) is classified Conflicting classifications of pathogenicity in PLEC (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.2042); Rare (popmax 0.483%, mid); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Ser386Arg (c.1158C>G)?

PLEC p.Ser386Arg (c.1158C>G) is associated with Inborn genetic diseases, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Ser386Arg (c.1158C>G) in the general population?

PLEC p.Ser386Arg (c.1158C>G) is rare (popmax 0.483%, mid) (gnomAD).

What do computational predictors say about PLEC p.Ser386Arg (c.1158C>G)?

AlphaMissense predicts likely benign (score 0.2042) — an in-silico prediction, not a clinical call.

PLEC p.Ser386Arg

c.1158C>G · rs201667254 · VCV193994

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.2042 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.483%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2042	likely benign
REVEL	0.36	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.23
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S523R vs ClinVar S386R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.483% Middle Eastern · 29/6,000 alleles

Filtering AF 0.372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.359%

Overall 0.114% 1,842/1,612,180 alleles · rare exomes 1,712/1,459,912 · genomes 130/152,268 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.483%	207
South Asian	0.406%	246
Remaining individualsnot grpmax-eligible	0.136%	735
European (non-Finnish)	0.111%	902
Admixed American	0.0666%	1,501
African / African-American	0.0107%	9,378
Finnishnot grpmax-eligible	0.00321%	31,152

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PLEC
Protein: p.Ser386Arg
Coding: c.1158C>G
MANE Select: NM_201384
dbSNP: rs201667254
Type: single nucleotide variant
Location: chr8:143934329 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)

Full PLEC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epidermolysis bullosa simplex 5A, Ogna type epidermolysis bullosa simplex 5B, with muscular dystrophy epidermolysis bullosa simplex 5C, with pyloric atresia autosomal recessive limb-girdle muscular dystrophy type 2Q epidermolysis bullosa simplex with nail dystrophy

Similar variants

PLEC p.Ser386Ile Uncertain significance ★ ⚠ same residue
PLEC p.Arg1490Ter Pathogenic/Likely pathogenic ★★ same condition
PLEC p.Arg1973Trp Pathogenic ★★ ⚠ same condition
PLEC p.Arg2027Ter Pathogenic ★★ same condition
PLEC p.Arg2292Ter Pathogenic ★★ same condition
PLEC p.Arg2324Ter Pathogenic ★★ same condition
PLEC p.Arg2394Ter Pathogenic ★★ same condition
PLEC p.Arg559Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/plec-p-ser386arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown